Innate immune priming by n-dodecyl-β-D-maltoside in murine models of bacterial and viral infection.

BACKGROUND: The COVID-19 pandemic underscored how hospital-acquired co-infections with antimicrobial resistance (AMR) bacteria and respiratory viruses can drive high mortality in critically ill patients. Despite antimicrobial stewardship and vaccines, effective prophylactic solutions remain lacking, highlighting the need for safe, antigen-independent strategies that provide rapid, broad-spectrum protection. METHODS: We tested whether a single intraperitoneal pretreatment with n-dodecyl-β-D-maltoside (DDM) could provide broad prophylaxis. Mice were challenged with clinical isolates of carbapenem-resistant Escherichia coli (CREC) and Pseudomonas aeruginosa (CRPA), methicillin-resistant Staphylococcus aureus (MRSA), or pandemic H1N1 influenza. Mechanistic studies assessed intracellular bacterial killing, immune cell dynamics (flow cytometry, histopathology), and neutrophil depletion, transcriptome, and cytokine profiling. FINDINGS: A single prophylactic administration of DDM conferred complete protection against lethal CREC, CRPA, and MRSA, while reducing viral titres and mortality in influenza-infected mice. DDM primed innate immunity through rapid neutrophil recruitment and activation, enhancing phagocytosis, bacterial clearance, and expression of effector genes linked to chemotaxis, ROS, and NET formation, predominantly mediated by Gi-dependent signalling pathway. Unlike pathogen-associated molecular pattern (PAMP)-based agents, DDM did not induce systemic inflammation or long-term immune reprogramming. Neutrophil depletion abolished protection, confirming their central role. Furthermore, DDM upregulated interferon-stimulated genes in lung tissue only upon viral infection, conferring selective antiviral immunity while attenuating cytokine-driven pathology. INTERPRETATION: DDM is a first-in-class, non-PAMP immune primer that rapidly and safely induces neutrophil-driven protection against AMR bacterial sepsis and viral infection, offering a host-directed strategy for cross-pathogen prophylaxis in high-risk settings. FUNDING: National Research Foundation of Korea (RS-2023-00219213); Korea Environmental Industry and Technology Institute (2022002980009; 1485018881); Korea Research Institute of Bioscience and Biotechnology Research Initiative Program.